It is estimated that 1 in 9 individuals in the United States have some manifestation of chronic kidney disease (CKD), ranging from proteinuria with normal renal clearance/function to advanced renal failure requiring renal replacement therapy in the form of dialysis or transplantation, commonly called end-stage renal disease (ESRD). The American Heart Association recently published a Scientific Statement that details strong evidence supporting that individuals with chronic kidney disease should be included in the highest-risk group for cardiovascular disease and therefore should receive aggressive preventive measures to reduce the prevalence and severity of cardiovascular disease.
Cardiovascular mortality is the leading cause of death in patients treated by dialysis, with mortality 10 to 30 times higher than the general population despite stratification for sex, race, and presence of diabetes. Similarly, cardiovascular mortality is 2 to 5 times higher than the general population in patients with a functioning renal transplant. This is likely from (1) the extremely high prevalence of atherosclerosis, heart failure, and left ventricular failure in hemodialysis patients, observed in 40% to 74% of incident dialysis patients and (2) a high case mortality rate after an acute myocardial infarct or of heart failure.
Coronary artery calcification is very common in dialysis patients. Depending on the age of the patient population examined, 54% to 100% (mean 83%) of dialysis patients in case series have some degree of coronary artery calcification, with scores markedly above the general population. Coronary artery calcification is also present in adolescents and young adults with chronic kidney disease. Once coronary artery calcification is present in dialysis patients, it is rapidly progressive in nearly all studies, with minimal or no progression after renal transplantation.
Under normal physiological condition, serum calcium and phosphorous are tightly controlled and balanced. However, the degenerated kidney in renal disease patients will fail to adequately response to regulation system and decrease phosphorus excretion. With the worsening of kidney condition and phosphorus accumulation, parathyroid will continuously increase production of parathyroid hormone (PTH). High PTH induces calcium release from bone to serum. As a result, most of the patients with renal failure will be found to have elevated serum phosphorus, calcium and PTH. Hyperphosphatemia, increased Calcium and Phosphorus (Ca×P) product in serum, hyperparathyroidism and increased calcium intake have been considered as significant predictors of cardiovascular morbidity and mortality, potentially acting as progression factors of unwanted calcifications in uremia (Block and Port (2000), Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendations for a change in management. American Journal of Kidney Diseases, 35:1226-1237; Ketteler et al. (2005), Pathogenesis of vascular calcification in dialysis patients. Clin. Exp. 9:265-270).
Phosphorous exerts a negative impact on vascular calcification by direct participation in the change of Ca×P and indirectly in the pathogenesis and progression of hyperthyroidism. Serum calcium and phosphorous are metastable under normal circumstances, which means that their concentrations are not sufficient to produce spontaneous precipitation. However, once the calcification process begins, the concentrations are sufficient to support crystal proliferation.
It is believed that the abnormally high calcium and phosphorus concentration contribute to randomly passive precipitation of calcium phosphate in body. Although the whole mechanism of action is still under exploration, recent studies have found a more complicated and active pathway that the disturbances of mineral metabolism (hyperphosphatemia and hypercalcemia) appear to further induce genetic changes in vascular smooth muscle cell and change the cell behavior toward an osteoblast-like phenotype contributing to progressive calcification (Ketteler et al. (2005), Pathogenesis of vascular calcification in dialysis patients. Clin. Exp. 9:265-270).
The degree of abnormal soft-tissue calcification progressed as degree of renal disease increased and can happen through out the body in organs such as skin, joint, eye, heart valve, myocardium, coronary arteries, arterioles, lung, kidney, etc. Among them, ocular calcification is among the most frequently observed and highly prevalent soft-tissue calcification in hemodialysis patients (Tilman Drueke and Isidro Salusky, The Spectrum of Renal Osteodystrophy. Oxford University Press. p345-357). Ectopic calcifications mostly occurs on the limbal area exposed by the interpalpebral fissure on conjunctiva and cornea, and appear as fine white deposits, coarse granular crystals, or flatter plaques. If not well managed, calcification on the eye area may lead to decrease of vision, irritation and ocular discomfort which may worsen to the point of becoming disabling. In addition, calcium deposits may cause epithelial and persistent tissue defects.
A recent study further investigated the relationship between the severity of eye calcification and occurrence of vascular calcification in dialysis patients and found a significant correlation between the degree of ocular calcification and status of extra-skeletal calcification. The study suggested the degree of ocular calcification may be used as a tool to assess the status of extra-skeletal calcification such as soft tissue calcification or any other organ calcifications (Seyahi et al. (2005), Association of conjunctival and corneal calcification with vascular calcification in dialysis patients. American Journal of Kidney Disease 45:550-556).
The development of calcification in cardiovascular system can lead to development of a number of clinically significant complications such as myocardial ischemia, myocardial infarction, impaired myocardial function, congestive heart failure and cardiac valve insufficiency. The accelerated development of cardiovascular disease, particularly coronary artery disease and chronic heart failure, is the leading cause of death in patients with end stage renal disease. It has been reported that the yearly all-cause mortality in dialysis patients ranges between 12% and 25%. Among them approximately 50% of this excess mortality is due to cardiovascular causes (Ketteler et al., 2005).
Calcification also extends beyond renal disease patients and can include anyone who is over the age of 40. While the leading cause of death in the United States is acute myocardial infarction and stroke, hypercholesteromia contribute to only 15% of the deaths in this category and 85% is caused by ventricular calcification.
Accordingly, there exists a need for a method of managing or reducing serum phosphorous, Calcium and Phosphorus product (Ca×P) and parathyroid hormone (PTH) levels in subjects that have an increased risk of developing vascular, visceral or soft tissue calcification. The present invention provides methods of using novel forms of ferric organic compounds that satisfy this need.